The development of viral resistance to drugs can significantly reduce the efficacy of therapy for chronic hepatitis B virus (HBV) infection, slowing the rate of seroconversion, reversing previous gains in liver function and histology, and allowing disease progression. The efficacy of the nucleoside analogue lamivudine has been compromised by the development of viral resistance. Research into the mechanisms of nucleoside resistance has intensified and has included the development of new resistance assays. Resistance to lamivudine appears to be caused by the compound's structural features. Mutations are selected in HBV polymerase that can discriminate among the structural differences between lamivudine triphosphate and the natural substrate mimicked by lamivudine, dCTP, causing steric hindrance and reduced efficiency of incorporation of lamivudine but not the natural substrate. Unlike lamivudine, adefovir dipivoxil, an oral anti-HBV agent in late-stage development, has not been associated with HBV resistance, either in vitro or in vivo. One long-term clinical study has shown a lack of resistance to adefovir dipivoxil in patients treated for up to 136 weeks. In addition, adefovir dipivoxil is a nucleotide (rather than a nucleoside) analogue that exhibits no cross-resistance with lamivudine and is effective against lamivudine-resistant HBV. In one hypothesis, this lack of resistance has been attributed to the minimal flexible acyclic structure of adefovir that subverts resistance due to steric hindrance. By reducing the rate and frequency of development of drug resistance, adefovir dipivoxil and other new oral antiviral agents maximize the clinical advantages of long-term sustained viral suppression (HBV DNA reduction) to achieve lasting therapeutic benefits.